Alcohol is one of the most widely used and misused drugs in the US. There is a critical need to continue to improve AUD treatment and develop new medications to reduce alcohol use and to include nicotine co-use in evaluations of candidate medications. This project proposes to investigate biobehavioral mechanisms underlying alcohol and nicotine use and co-use, and to test candidate medications in two animal models developed specifically for testing medications for alcohol abuse, and alcohol and nicotine co-use. The first model uses a Chained Schedule of Reinforcement (CSR) procedure in which seeking and consumption occur in the context of distinct environmental cues and behavioral contingencies to the influence of environmental stimuli on the drive to drink and the persistence of behaviors associated with chronic drinking. Two 2 matched groups of NHP with extensive histories of self-administration of alcohol (Alcohol group) or the non-alcoholic beverage (Control group) will be utilized. The second model is a new Alcohol and Nicotine Concurrent Access (ANCA) procedure in which oral alcohol and IV nicotine were concurrently available for self-administration. A functional assessment battery provides assessment of drug side effects. Aim 1 will determine whether test drugs reduce alcohol seeking and self-administration in the CSR under conditions of ongoing drinking and abstinence. Aim 2 will determine whether test drugs reduce alcohol and nicotine self-administration independently or concurrently under single drug access or ANCA procedures. Aim 3 will determine incidence of side effects of test drugs in the functional assessment battery. Drug candidates include bifunctional and universal opioid receptor (OR) ligands with different pharmacological profiles at OR subtypes, a universal OR/nociception opioid peptide (NOP) receptor ligand, the cannabinoid constituent cannabidiol (CBD), the neuropeptide oxytocin, and a nicotinic acetylcholine receptor partial agonist/antagonist varenicline. Naltrexone will be tested as a positive control and comparator. A drug with therapeutic potential would be one that reduces cue-maintained seeking, and decreases alcohol self-administration, and has a low side-effect profile. A drug with therapeutic potential in alcohol and nicotine co-users would decrease alcohol self-administration without increasing nicotine self-administration, and ideally would reduce self-administration of both drugs. Integration these data will provide new information on the behavioral and neuropharmacological mechanisms involved in alcohol abuse and alcohol/nicotine co-use. Comparison of dose effect functions and efficacy across models can inform treatment strategies for optimal dosing and timing of treatment. This information will ultimately facilitate medication development for the treatment of alcohol misuse and AUD.